The present invention is directed to certain novel compounds represented by structural Formula (I) 
or pharmaceutically acceptable salt forms thereof, wherein R1, R5, R6a, R6b, R7, R8, R9, X, b, k, m, and n, and the dashed lines are described herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
There exists a substantial correlation for the relationship between 5-HT2 receptor modulation and a variety of diseases and therapies. To date, three subtypes of the 5-HT2 receptor class have been identified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990""s the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2, respectively.
The agonism or antagonism of 5-HT2 receptors, either selectively or nonselectively, has been associated with the treatment of various central nervous system (CNS) disorders. Ligands possessing affinity for the 5-HT2 receptors have been shown to have numerous physiological and behavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990). In the recent past the contribution of serotonergic activity to the mode of action of antidepressant drugs has been well documented. Compounds that increase the overall basal tone of serotonin in the CNS have been successfully developed as antidepressants. The serotonin selective reuptake inhibitors (SSRI) function by increasing the amount of serotonin present in the nerve synapse. These breakthrough treatments, however, are not without side effects and suffer from delayed onset of action (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to the mechanism of action of the SSRIs, they effect the activity of a number of serotonin receptor subtypes. This non-specific modulation of the serotonin family of receptors most likely plays a significant role in the side effect profile. In addition, these compounds often have a high affinity for a number of the serotonin receptors as well as a multitude of other monoamine neurotransmitters and nuisance receptors. Removing some of the receptor cross reactivity would allow for the examination and possible development of potent therapeutic ligands with an improved side effect profile.
There is ample evidence to support the role of selective 5-HT2 receptor ligands in a number of disease therapies. Modulation of 5-HT2 receptors has been associated with the treatment of schizophrenia and psychoses (Ugedo, L., et. al., Psychopharmacology, 98, 45, 1989). Mood, behavior and hallucinogenesis can be affected by 5-HT2 receptors in the limbic system and cerebral cortex. 5-HT2 receptor modulation in the hypothalamus can influence appetite, thermoregulation, sleep, sexual behavior, motor activity, and neuroendocrine function (Hartig, P., et.al., Annals New York Academy of Science, 149, 159). There is also evidence indicating that 5-HT2 receptors mediate hypoactivity, effect feeding in rats, and mediate penile erections (Pyschopharmacology, 101, 57, 1990).
Compounds exhibiting selectivity for the 5-HT2B receptor are useful in treating conditions such as tachygastria, hypermotility associated with irritable bowel disorder, constipation, dyspepsia, and other peripherally mediated conditions.
5-HT2A antagonists have been shown to be effective in the treatment of schizophrenia, anxiety, depression, and migraines (Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from the beneficial antipsychotic effects, classical neuroleptic are frequently responsible for eliciting acute extrapyramidal side effects and neuroendocrine disturbances. These compounds generally possess signifcant dopamine D2 receptor affinity (as well as other nuisance receptor affinity) which frequently is associated with extra pyramidal symptoms and tardive dyskinesia, thus detracting from their efficacy as front line treatments in schizophrenia and related disorders. Compounds possessing a more favorable selectivity profile would represent a possible improvement for the treatment of CNS disorders.
U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and 4,238,607 disclose pyridopyrrolobenzheterocycles of formula: 
where X is O, S, S(xe2x95x90O), or SO2; n is 0 or 1; R1 is various carbon substituents, and Z is a monosubstituent of H, methyl, or chloro.
U.S. Pat. No. 4,219,550 discloses pyridopyrrolobenzheterocycles of formula: 
where X is O or S; R1 is C1-4 alkyl or cyclopropyl; R2 is H, CH3, OCH3, Cl, Br, F, or CF3; and (A) is xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, or xe2x80x94CH2CH2xe2x80x94.
One object of the present invention is to provide novel compounds which are useful as agonists or antagonists of 5-HT2 receptors, more specifically 5-HT2A and 5-HT2C receptors, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof. More specifically, the present invention provides a method for treating obesity anxiety, depression, or schizophrenia.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R1, R5, R6a, R6b, R7, R8, R9, X, b, k, m, and n are defined below, are effective agonists or antagonists of 5-HT2 receptors.
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): 
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein:
b is a single bond or a double bond;
X is xe2x80x94CHR10xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NR10Axe2x80x94, xe2x80x94C(xe2x95x90O)NR10Axe2x80x94, or xe2x80x94NR10AC(xe2x95x90O)xe2x80x94;
R1 is selected from
H
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-3 alkyl substituted with Y,
C2-3 alkenyl substituted with Y,
C2-3 alkynyl substituted with Y,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
Y is selected from
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with z;
C3-6 cycloalkyl substituted with xe2x80x94(C1-3 alkyl)-Z,
aryl substituted with xe2x80x94(C1-3 alkyl)-Z, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with xe2x80x94(C1-3 alkyl)-Z;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H and C1-4 alkyl;
R5 is H or C1-4 alkyl;
R6a and R6b, at each occurrence, are independently selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, and
aryl substituted with 0-3 R44;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl, substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33, aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)R13, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl, substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)R13, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R10 is selected from H, xe2x80x94OH,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)R13, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12; p0 R12, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, and C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46SO2R45, NR46COR45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H and C1-4 alkyl;
k is 1 or 2;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
provided when m is 0, then k is 1;
provided that when b is a double bond; n is 1 or 2; m is 1; k is 1; X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, or xe2x80x94SO2xe2x80x94; and the three substituents of R7, R8, and R9, consist of i) three hydrogens, ii) two hydrogens and one chloro, or iii) two hydrogens and one methyl; then R1 must contain the substituent Z or Y;
provided that when b is a double bond; n is 0 or 1; m is 1; k is 1; X is xe2x80x94CH2xe2x80x94; and R1 is hydrogen, C1-6 alkyl or benzyl; then one of R7, R8, and R9, must be other than hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or trifluoromethyl;
provided that when b is a single bond; n is 1 or 2; m is 1; k is 1; X is O or S; and R1 is C1-4 alkyl or cyclopropyl, then R8 is a substituent other than H;
provided that when R6 or R6a is NH2, then X is not xe2x80x94CH(R10); and
provided that when nxe2x95x900, then R6 or R6a is not NH2 or xe2x80x94OH.
In another embodiment of the present invention,
X is xe2x80x94CHR10xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-3 alkyl substituted with Y,
C2-3 alkenyl substituted with Y,
C2-3 alkynyl substituted with Y,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
Y is selected from
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C3-6 cycloalkyl substituted with xe2x80x94(C1-3 alkyl)-Z,
aryl substituted with xe2x80x94(C1-3 alkyl)-Z, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with xe2x80x94(C1-3 alkyl)-Z;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2R3,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
halo,
C1-3 haloalkyl,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H and C1-4 alkyl;
R5 is H or C1-4 alkyl;
R6a and R6b, at each occurrence, are independently selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, and
aryl substituted with 0-3 R44;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R12 at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
C1-3 haloalkyl-oxy-, and C1-3 alkyloxy-;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 
cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SOR45, SR45, NR46SO2R45, NR46COR45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O) NH (C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl) xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)( C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
k is 1 or 2;
m is 0, 1, or 2;
n is 1, 2, or 3;
provided when m is 0 or 1 then k is 1 or 2;
provided when m is 2 then k is 1;
provided that when nxe2x95x90O, then R6 or R6a is not NH2 or xe2x80x94OH.
(2) In a preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94, xe2x80x94C(xe2x95x90O)NR10Axe2x80x94, or xe2x80x94NR10AC(xe2x95x90O)xe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-3 alkyl substituted with Y,
C2-3 alkenyl substituted with Y,
C2-3 alkynyl substituted with Y,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted wit h 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
Y is selected from
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z; C3-6 cycloalkyl substituted with xc2x7(C1-3 alkyl)-Z, aryl substituted with xc2x7(C1-3 alkyl)-Z, and 5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with xc2x7(C1-3 alkyl)-Z;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2R3,
xe2x80x94C(O)R2 
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
halo,
C1-3 haloalkyl,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H and C1-4 alkyl;
R5 is H or C1-4 alkyl;
R6a and R6b, at each occurrence, are independently selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, and
aryl substituted with 0-3 R44;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14CCO)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15 NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2, R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
C1-3 haloalkyl-oxy-, and C1-3 alkyloxy-;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SOR45, SR45, NR46SO2R45, NR46COR45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl),
xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)( C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
k is 1 or 2;
m is 0, 1, or 2;
n is 1, 2, or 3;
provided when m is 0 or 1 then k is 1 or 2;
provided when m is 2 then k is 1;
provided that when nxe2x95x900, then R6 or R6a is not NH2 or xe2x80x94OH.
In a further preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHC(xe2x95x90O)xe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-8 alkyl,
C2-8 alkenyl,
C2-8 alkynyl,
C3-7 cycloalkyl,
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
R2, at each occurrence, is independently selected from
F, Cl, CH2F, CHF2, CF3,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R5 is H, methyl, ethyl, propyl, or butyl;
R6a is selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3,
C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and
aryl substituted with 0-3 R44;
R6b is H;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl,
C1-3 haloalkyl-oxy-, and C1-3 alkyloxy-;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C14 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN;
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H and C1-4 alkyl;
k is 1 or 2;
m is 0, 1, or 2; and
n is 1, 2, or 3.
[4] In a more preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94;
R1 is selected from
H,
C(xe2x95x90O)R2,
C(xe2x95x90O)OR2,
C1-6 alkyl,
C2-6 alkenyl,
C2-6 alkynyl,
C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-2 R2,
C2-4 alkenyl substituted with 0-2 R2, and
C2-4 alkynyl substituted with 0-2 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R5 is H, methyl, ethyl, propyl, or butyl;
R6a is selected independently from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3, C1-3 alkyl, and C1-3 alkoxy;
R6b is H;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, SO(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R10A is selected from H,
C1-4 alkyl substituted with 0-1 R10B,
C2-4 alkenyl substituted with 0-1 R10B,
C2-4 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, C1-6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, (O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and
trifluoromethoxy;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, and C1-4 alkyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 
cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, C2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H and C1-4 alkyl;
k is 1 or 2;
m is 0 or 1; and
n is 1 or 2.
[5] In an even more preferred embodiment of the present invention,
X is xe2x80x94NHxe2x80x94;
R1 is selected from
H,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-4 cycloalkyl,
C1-3 alkyl substituted with 0-1 R2,
C2-3 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-6 carbocyclic residue substituted with 0-3 R41, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R5 is H, methyl, ethyl, propyl, or butyl;
R6a is H, methyl, ethyl, methoxy, xe2x80x94OH, or xe2x80x94CF3;
R6b is H;
R7 and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R8 is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of one N, two N, three N, one N one O, and one N one S; wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-2 R16;
R14, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, C2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
k is 1;
m is 1; and
n is 1 or 2.
[6] In another even more preferred embodiment of the present invention,
X is xe2x80x94NHxe2x80x94;
R1 is selected from
H,
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-4 cycloalkyl,
C1-3 alkyl substituted with 0-1 R2,
C2-3 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R42;
C3-6 carbocyclic residue substituted with 0-3 R41, and 5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R5 is H, methyl, ethyl, propyl, or butyl;
R6a is H, methyl, ethyl, methoxy, xe2x80x94OH, or xe2x80x94CF3;
R6b is H;
R7 and R9, at each occurrence, are independently selected from
H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2,
R8 is selected from
H, F, Cl, Br, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C1-4 alkyl substituted with 0-2 R11,
C2-4 alkenyl substituted with 0-2 R11,
C2-4 alkynyl substituted with 0-1 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O) NHR15;
R11is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 cycloalkyl substituted with 0-2 R33,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12, at each occurrence, is independently selected from
C1-4 alkyl substituted with 0-1 R12a,
C2-4 alkenyl substituted with 0-1 R12a,
C2-4 alkynyl substituted with 0-1 R12a,
C3-6 cycloalkyl substituted with 0-3 R33,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R12a, at each occurrence, is independently selected from
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S; wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said bicyclic heterocyclic ring system is substituted with 0-1 R16;
R14, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R15, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, xe2x80x94C(xe2x95x90O)H,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-6 cycloalkyl, C1-4 haloalkyl, C1-4 haloalkyl-oxy-,
C1-4 alkyloxy-,
C1-4 alkylthio-, C1-4 alkyl-C(xe2x95x90O)xe2x80x94, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94,
C1-4 alkyl-OC(xe2x95x90O)xe2x80x94,
C1-4 alkyl-C(xe2x95x90O)Oxe2x80x94, C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
C1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
C2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, C2H, SO2R45, NR46R47, NO2, CN,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 alkyl;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C3-6 cycloalkyl, and C1-3 alkyl;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
k is 1;
m is 1; and
n is 1 or 2.
[7] In another even more preferred embodiment of the present invention,
X is xe2x80x94NHxe2x80x94;
R1 is selected from H,
C1-5 alkyl substituted with 0-1 R2,
C2-5 alkenyl substituted with 0-1 R2, and
C2-3 alkynyl substituted with 0-1 R2;
R2 is C3-6 cycloalkyl;
R5 is H, methyl, ethyl, or propyl;
R6a is H, methyl, or ethyl;
R6b is H;
R7 and R9, at each occurrence, are independently selected from
H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2,
R8 is selected from
methyl substituted with R11;
ethenyl substituted with R11;
OR12, SR12, NR12R13, NR12C(O)R15, NR12C(O)OR15,
NR12S(O)2R15, and NR12C(O)NHR15;
R11 is selected from
phenyl-substituted with 0-5 fluoro;
2-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
2-(HC(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CCH(OH))-phenyl-substituted with R33;
2-(H3CCH2CH(OH))-phenyl-substituted with R33;
2-(HOCH2)-phenyl-substituted wit h R33;
2-(HOCH2CH2)-phenyl-substituted with R33;
2-(H3COCH2)-phenyl-substituted with R33;
2-(H3COCH2CH2)-phenyl-substituted with R33;
2-(H3CCH(OMe))-phenyl-substituted with R33;
2-(H3COC(xe2x95x90O))-phenyl-substituted with R33;
2-(HOCH2CHxe2x95x90CH)-phenyl-substituted with R33;
2-((MeOCxe2x95x90O)CHxe2x95x90CH)-phenyl-substituted with R33;
2-(methyl)-phenyl-substituted with R33;
2-(ethyl)-phenyl-substituted with R33;
2-(i-propyl)-phenyl-substituted with R33;
2-(F3C)-phenyl-substituted with R33;
2-(NC)-phenyl-substituted with R33;
2-(H3CO)-phenyl-substituted with R33;
2-(fluoro)-phenyl-substituted with R33;
2-(chloro)-phenyl-substituted with R33;
3-(NC)-phenyl-substituted with R33;
3-(H3CO)-phenyl-substituted with R33;
3-(fluoro)-phenyl-substituted with R33;
3-(chloro)-phenyl-substituted with R33;
4-(NC)-phenyl-substituted with R33;
4-(fluoro)-phenyl-substituted with R33;
4-(chloro)-phenyl-substituted with R33;
4-(H3CS)-phenyl-substituted with R33;
4-(H3CS)-phenyl-substituted with R33;
4-(ethoxy)-phenyl-substituted with R33;
4-(i-propoxy)-phenyl-substituted with R33;
4-(i-butoxy)-phenyl-substituted with R33;
4-(H3CCH2CH2C(xe2x95x90O))-phenyl-substituted with R33;
4-((H3C)2CHC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2CH2CH(OH))-phenyl-substituted with R33;
4-((H3C)2CHCH(OH))-phenyl-substituted with R33;
4-(H3CCH2CH(OH))-phenyl-substituted with R33;
4-(H3CCH(OH))-phenyl-substituted with R33;
4-(cyclopropyloxy)-phenyl-substituted with R33;
4-(cyclobutyloxy)-phenyl-substituted with R33; and
4-(cyclopentyloxy)-phenyl-substituted with R33;
R12 is selected from
phenyl-substituted with 0-5 fluoro;
2-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
2-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
2-(HC(xe2x95x90O))-phenyl-substituted with R33;
5 2-(H3CCH(OH))-phenyl-substituted with R33;
2-(H3CCH2CH(OH))-phenyl-substituted with R33;
2-(HOCH2)-phenyl-substituted with R33;
2-(HOCH2CH2)-phenyl-substituted with R33;
2-(H3COCH2)-phenyl-substituted with R33;
2-(H3COCH2CH2)-phenyl-substituted with R33;
2-(H3CCH(OMe))-phenyl-substituted with R33;
2-(H3COC(xe2x95x90O))-phenyl-substituted with R33;
2-(HOCH2CHxe2x95x90CH)-phenyl-substituted with R33;
2-((MeOCxe2x95x90O)CHxe2x95x90CH)-phenyl-substituted with R33;
2-(methyl)-phenyl-substituted with R33;
2-(ethyl)-phenyl-substituted with R33;
2-(i-propyl)-phenyl-substituted with R33;
2-(F3C)-phenyl-substituted with R33;
2-(NC)-phenyl-substituted with R33;
2-(H3CO)-phenyl-substituted with R33;
2-(fluoro)-phenyl-substituted with R3 3;
2-(choloro)-phenyl-substituted with R33;
3-(NC)-phenyl-substituted with R33;
3-(H3CO)-phenyl-substituted with R33;
3-(floro)-phenyl-substituted with R33;
3-(chloro)-phenyl-substituted with R33; 
4-(NC)-phenyl-substituted with R33;
4-(fluoro)-phenyl-substituted with R33;
4-(choloro)-phenyl-substituted with R33;
4-(H3CS)-phenyl-substituted with R33;
4-(H3CO)-phenyl-substituted with R33;
4-(ethoxy)-phenyl-substituted with R33;
4-(i-propoxy)-phenyl-substituted with R33;
4-(i-butoxy)-phenyl-substituted with R33;
4-(H3CCH2CH2C(xe2x95x90O))-phenyl-substituted with R33;
4-( (H3C)2CHC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2C(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CC(xe2x95x90O))-phenyl-substituted with R33;
4-(H3CCH2CH2CH(OH))-phenyl-substituted with R33;
4-((H3C)2CHCH(OH))-phenyl-substituted with R33;
4-(H3CCH2CH(OH))-phenyl-substituted with R33;
4-(H3CCH(OH))-phenyl-substituted with R33;
4-(cyclopropyloxy)-phenyl-substituted with R33.;
4-(cyclobutyloxy)-phenyl-substituted with R33; and
4-(cyclopentyloxy)-phenyl-substituted with R33;
R13 is H, methyl, or ethyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl, methylpiperizinyl,and morpholinyl;
alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S; wherein said bicyclic heterocyclic ring system is selected from indolyl, indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said bicyclic heterocyclic ring system is substituted with 0-1 R16;
R15 is H, methyl, ethyl, propyl, or butyl;
R16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
R33, at each occurrence, is independently selected from
H, F, Cl, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, and xe2x80x94NO2;
k is 1;
m is 1; and
n is 1 or 2.
[8] In an even more preferred embodiment of the present invention, the compound of Formula (I) is selected from Formula (I-a): 
wherein:
b is a single bond or a double bond;
X is xe2x80x94NR10Axe2x80x94;
R1 is selected from
hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,
2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,
2-ethylbutyl, 3-methylpentyl, 3-methylbutyl,
4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl,
2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl,
3-methyl-butenyl, 3-butenyl, trans-2-pentenyl,
cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl,
benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,
2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl,
2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxybenzyl, pentafluorobenzyl, 2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl, 2-phenylbenzyl,
(2,3-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, (2,5-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, (3,4-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94,
(3,5-dimethoxy-phenyl)C(xe2x95x90O)xe2x80x94, cyclopropyl-C(xe2x95x90O)xe2x80x94,
isopropyl-C(xe2x95x90O)xe2x80x94, ethyl-CO2xe2x80x94, propyl-CO2xe2x80x94, t-butyl-CO2xe2x80x94,
2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,
2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,
2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl,
3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,
(4-fluoro-phenyl)ethyl,
xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94Cxe2x89xa1xe2x80x94CH, xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, and
xe2x80x94CH2xe2x80x94Cxe2x89xa1CH;
R7, R8, and R9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenyl,
methylC(xe2x95x90O)xe2x80x94, ethylC(xe2x95x90O)xe2x80x94, propylC(xe2x95x90O)xe2x80x94, isopropylC(xe2x95x90O)xe2x80x94,
butylC(xe2x95x90O)xe2x80x94, phenylC(xe2x95x90O)xe2x80x94,
methylCO2xe2x80x94, ethylCO2xe2x80x94, propylCO2xe2x80x94, isopropylCO2xe2x80x94,
butylCO2xe2x80x94, phenylCO2xe2x80x94,
dimethylamino-S(xe2x95x90O)xe2x80x94, diethylamino-S(xe2x95x90O)xe2x80x94,
dipropylamino-S(xe2x95x90O)xe2x80x94, di-isopropylamino-S(xe2x95x90O)xe2x80x94,
dibutylamino-S(xe2x95x90O)xe2x80x94, diphenylamino-S(xe2x95x90O)xe2x80x94,
dimethylamino-SO2xe2x80x94, diethylamino-SO2xe2x80x94, dipropylamino-SO2xe2x80x94, di-isopropylamino-SO2xe2x80x94, dibutylamino-SO2xe2x80x94, diphenylamino-SO2xe2x80x94,
dimethylamino-C(xe2x95x90O)xe2x80x94, diethylamino-C(xe2x95x90O)xe2x80x94,
dipropylamino-C(xe2x95x90O)xe2x80x94, di-isopropylamino-C(xe2x95x90O)xe2x80x94,
dibutylamino-C(xe2x95x90O)xe2x80x94, diphenylamino-C(xe2x95x90O)xe2x80x94,
2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,
2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,
3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,
3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,
4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,
4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyphenyl,
2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyphenyl,
2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyphenyl,
2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
2-chloro-4-CF3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF3O-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,
methyl-C(xe2x95x90O)NHxe2x80x94, ethyl-C(xe2x95x90O)NHxe2x80x94, propyl-C(xe2x95x90O)NHxe2x80x94,
isopropyl-C(xe2x95x90O)NHxe2x80x94, butyl-C(xe2x95x90O)NHxe2x80x94, phenyl-C(xe2x95x90O)NHxe2x80x94,.
4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO2-phenyl, 2-NO2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF2)O-phenyl,
2,4-diMeO-6-F-phenyl, 2-CF3-6-F-phenyl,
2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,
2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,
2-CF3-4-EtO-phenyl, 2-CF3-4-iPrO-phenyl,
2-CF3-4-Cl-phenyl, 2-CF3-4-F-phenyl, 2-Cl-4-EtO-phenyl,
2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,
2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(xe2x95x90O)Me-4-MeO-phenyl,
2-CH2(OH)-4-MeO-phenyl, 2-CH2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(xe2x95x90O)Et-4-MeO-phenyl,
(Z)-2-CHxe2x95x90CHC2Me-4-MeO-phenyl,
2-CH2CH2CO2Me-4-MeO-phenyl,
(Z)-2-CHxe2x95x90CHCH2(OH)-4-MeO-phenyl,
(E)-2-CHxe2x95x90CHC2Me-4-MeO-phenyl,
(E)-2-CHxe2x95x90CHCH2 (OH)-4-MeO-phenyl,
2-CH2CH2OMe-4-MeO-phenyl,
2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,
(2-Cl-phenyl)-CHxe2x95x90CHxe2x80x94, (3-Cl-phenyl)-CHxe2x95x90CHxe2x80x94,
(2,6-diF-phenyl)-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CH2,
phenyl-CHxe2x95x90CHxe2x80x94, (2-Me-4-MeO-phenyl)-CHxe2x95x90CHxe2x80x94,
cyclohexyl, cyclopentyl, cyclohexylmethyl,
xe2x80x94CH2CH2CO2Et, xe2x80x94(CH2)3CO2Et, xe2x80x94(CH2)4CO2Et,
benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,
3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,
2-OH-benzyl, 2-CO2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF3-4-CN-phenyl,
3-CHO-phenyl, 3-CH2(OH)-phenyl, 3-CH2(OMe)-phenyl,
3-CH2(NMe2)-phenyl, 3-CN-4-F-phenyl,
3-CONH2-4-F-phenyl, 2-CH2(NH2)-4-MeO-phenyl-,
phenyl-NHxe2x80x94, (4-F-phenyl)-NHxe2x80x94, (2,4-diCl-phenyl)-NHxe2x80x94,
phenyl-C(xe2x95x90O)NHxe2x80x94, benzyl-NHxe2x80x94, (2-Me-4-MeO-phenyl)-NHxe2x80x94,
(2-F-4-MeO-phenyl)-NHxe2x80x94, (2-Me-4-F-phenyl)-NHxe2x80x94,
phenyl-Sxe2x80x94, xe2x80x94NMe2, 1-pyrrolidinyl, and
xe2x80x94N(tosylate)2,
provided that two of R7, R8, and R9, are independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy;
R10A is selected from hydrogen, methyl, ethyl, benzyl and 4-fluorobenzyl;
m is 1; and
n is 1 or 2.
[9] In an even more preferred embodiment of the present invention, the compound of Formula (I) is selected from Formula (IV): 
wherein:
b is a single bond, wherein the bridge hydrogens are in a cis position;
R1 is selected from
hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,
2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,
2-ethylbutyl, 3-methylpentyl, 3-methylbutyl,
4-methylpentyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-propenyl, 2-methyl-2-propenyl,
trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl,
trans-3-phenyl-2-propenyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94Cxe2x89xa1CH, xe2x80x94Cxe2x89xa1Cxe2x80x94CH3,
and xe2x80x94CH2xe2x80x94Cxe2x89xa1H;
R7 and R9, at each occurrence, are independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
R8 is selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenyl,
methylC(xe2x95x90O)xe2x80x94, ethylC(xe2x95x90O)xe2x80x94, propylC(xe2x95x90O)xe2x80x94, isopropylC(xe2x95x90O)xe2x80x94,
butylC(xe2x95x90O)xe2x80x94, phenylC(xe2x95x90O)xe2x80x94,
methylCO2xe2x80x94, ethylCO2xe2x80x94, propylCO2xe2x80x94, isopropylCO2xe2x80x94,
butylCO2xe2x80x94, phenylCO2xe2x80x94,
dimethylamino-S(xe2x95x90O)xe2x80x94, diethylamino-S(xe2x95x90O)xe2x80x94,
dipropylamino-S(xe2x95x90O)xe2x80x94, di-isopropylamino-S(xe2x95x90O)xe2x80x94,
dibutylamino-S(xe2x95x90O)xe2x80x94, diphenylamino-S(xe2x95x90O)xe2x80x94,
dimethylamino-SO2xe2x80x94, diethylamino-SO2xe2x80x94, dipropylamino-SO2xe2x80x94di-isopropylamino-SO2xe2x80x94, dibutylamino-SO2xe2x80x94,
diphenylamino-SO2xe2x80x94,
dimethylamino-C(xe2x95x90O)xe2x80x94, diethylamino-C(xe2x95x90O)xe2x80x94,
dipropylamino-C(xe2x95x90O)xe2x80x94, di-isopropylamino-C(xe2x95x90O)xe2x80x94,
dibutylamino-C(xe2x95x90O)xe2x80x94, diphenylamino-C(xe2x95x90O)xe2x80x94,
2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,
2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,
3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,
3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,
4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,
4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyphenyl,
2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyphenyl,
2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyphenyl,
2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyphenyl,
3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyphenyl,
2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
2-chloro-4-CF3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF3O-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,
methyl-C(xe2x95x90O)NHxe2x80x94, ethyl-C(xe2x95x90O)NHxe2x80x94, propyl-C(xe2x95x90O)NHxe2x80x94, isopropyl-C(xe2x95x90O)NHxe2x80x94, butyl-C(xe2x95x90O)NHxe2x80x94, phenyl-C(xe2x95x90O)NHxe2x80x94,
4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO2-phenyl, 2-NO2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF2)0-phenyl,
2,4-diMeo-6-F-phenyl, 2-CF3-6-F-phenyl,
2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,
2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,
2-CF3-4-EtO-phenyl, 2-CF3-4-iPrO-phenyl,
2-CF3-4-Cl-phenyl, 2-CF3-4-F-phenyl, 2-Cl-4-EtO-phenyl,
2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,
2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(xe2x95x90O)Me-4-MeO-phenyl,
2-CH2(OH)-4-MeO-phenyl, 2-CH2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(xe2x95x90O)Et-4-MeO-phenyl,
(Z)-2-CHxe2x95x90CHCO2Me-4-MeO-phenyl,
2-CH2CH2CO2Me-4-MeO-phenyl,
(Z)-2-CHxe2x95x90CHCH2 (OH)-4-MeO-phenyl,
(E)-2-CHxe2x95x90CHCO2Me-4-MeO-phenyl,
(E)-2-CHxe2x95x90CHCH2(OH)-4-MeO-phenyl,
2-CH2CH2OMe-4-MeO-phenyl,
2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,
(2-Cl-phenyl)-CHxe2x95x90CHxe2x80x94, (3-Cl-phenyl)-CHxe2x95x90CHxe2x80x94,
(2,6-diF-phenyl)-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CH2,
phenyl-CHxe2x95x90CHxe2x80x94, (2-Me-4-MeO-phenyl)-CHxe2x95x90CHxe2x80x94,
cyclohexyl, cyclopentyl, cyclohexylmethyl,
xe2x80x94CH2CH2CO2Et, xe2x80x94(CH2)3CO2Et, xe2x80x94(CH2)4CO2Et,
benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,
3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,
2-OH-benzyl, 2-CO2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF3-4-CN-phenyl,
3-CHO-phenyl, 3-CH2(OH)-phenyl, 3-CH2(OMe)-phenyl,
3-CH2(NMe2)-phenyl, 3-CN-4-F-phenyl,
3-CONH2-4-F-phenyl, 2-CH2(NH2)-4-MeO-phenylxe2x80x94,
phenyl-NHxe2x80x94, (4-F-phenyl)-NHxe2x80x94, (2,4-diCl-phenyl)-NHxe2x80x94,
phenyl-C(xe2x95x90O)NHxe2x80x94, benzyl-NHxe2x80x94, (2-Me-4-MeO-phenyl)-NHxe2x80x94,
(2-F-4-MeO-phenyl)-NHxe2x80x94, (2-Me-4-F-phenyl)-NHxe2x80x94,
phenyl-Sxe2x80x94, xe2x80x94NMe2, 1-pyrrolidinyl, and
xe2x80x94N(tosylate)2;
R10A is selected from hydrogen, methyl, ethyl, 4-fluorobenzyl and benzyl; and p0 n is 1 or 2.
[10] In another preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94, xe2x80x94C(xe2x95x90O)NR10Axe2x80x94, or xe2x80x94NR10AC(xe2x95x90O)xe2x80x94;
R1 is selected from
C1-6 alkyl substituted with Z,
C2-6 alkenyl substituted with Z,
C2-6 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-6 alkyl substituted with 0-2 R2,
C2-6 alkenyl substituted with 0-2 R2,
C2-6 alkynyl substituted with 0-2 R2,
aryl substituted with 0-2 R2, and
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
xe2x80x94C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
C1 1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R5 is H, methyl, ethyl, propyl, or butyl;
R6a is selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl, and
aryl substituted with 0-3 R44;
R6b is H;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14, S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11 is selected from
H, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2,
C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, CO)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, OC(O)OR12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13, S()2NR12R13, NR14S(O)R12, and NR14S(O)2R12;
R12, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, SO2R45, NR46R47, methyl, ethyl, and propyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, SO2R45, NR46R47,
C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C3-5 cycloalkyl, C1-3 haloalkyl, C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, C1-3 alkylthio-, C1-3 alkyl-C(xe2x95x90O)xe2x80x94, and C1-3 alkyl-C(xe2x95x90O)NHxe2x80x94;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H,
halo, xe2x80x94OH, NR46R47, C2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H and C1-4 alkyl;
R47, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl),
xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)( C1-4 alkyl),
and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl),
xe2x80x94C(xe2x95x90O)(C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
k is 1 or 2;
m is 0, 1, or 2; and
n is 1 or 2.
[11] In a further preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94;
R1 is selected from
C2-5 alkyl substituted with Z,
C2-5 alkenyl substituted with Z,
C2-5 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C1-5 alkyl substituted with 0-2 R2,
C2-5 alkenyl substituted with 0-2 R2, and
C2-5 alkynyl substituted with 0-2 R2;
Z is selected from H,
CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94OC(O)R2,
xe2x80x94CH(xe2x95x90NR4)NR2R3,
xe2x80x94NHC(xe2x95x90NR4)NR2R3,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
aryl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R5 is H, methyl, or ethyl;
R6a is selected from
H, xe2x80x94OH, xe2x80x94NR46R47, xe2x80x94CF3,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, and C3-6 cycloalkyl;
R6b is H;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C1-4 alkyl substituted with 0-2 R11,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, NR14S(O)2R12, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
R10A is selected from H,
C1-6 alkyl substituted with 0-1 R10B,
C2-6 alkenyl substituted with 0-1 R10B,
C2-6 alkynyl substituted with 0-1 R10B, and
C1-6 alkoxy;
R10B is selected from
C1-4 alkoxy,
C3-6 cycloalkyl,
C3-6 carbocyclic residue substituted with 0-3 R33,
phenyl substituted with 0-3 R33, and
5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R44;
R11is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR46R47,
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, (C1-4 haloalkyl)oxy,
C3-10 carbocyclic residue substituted with 0-3 R33,
aryl substituted with 0-5 R33,
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
OR12, SR12, NR12R13, C(O)H, C(O)R12, C(O)NR12R13, NR14C(O)R12, C(O)OR12, OC(O)R12, CH(xe2x95x90NR14)NR12R13, NHC(xe2x95x90NR14)NR12R13, S(O)R12, S(O)2R12, S(O)2NR12R13, and NR14S(O)2R12;
R12 at each occurrence, is independently selected from
C1-4 alkyl,
C2-4 alkenyl,
C2-4 alkynyl,
C3-6 cycloalkyl,
phenyl substituted with 0-5 R33;
C3-10 carbocyclic residue substituted with 0-3 R33, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
R13, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94 or xe2x80x94N(R14)xe2x80x94;
R14, at each occurrence, is independently selected from H and C1-4 alkyl;
R31, at each occurrence, is independently selected from
H, OH, halo, CF3, methyl, and ethyl;
R33, at each occurrence, is independently selected from
H, OH, halo, CN, NO2, CF3, methyl, and ethyl;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, C2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2, C1-4 alkyl, and C1-4 alkoxy;
R45 is C1-4 alkyl;
R46, at each occurrence, is independently selected from H
and C1-3 alkyl;
R47, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94SO2(C1-4 alkyl),
xe2x80x94SO2(phenyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl), xe2x80x94C(xe2x95x90O)( C1-4 alkyl)
and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from H,
C1-4 alkyl, xe2x80x94C(xe2x95x90O)NH(C1-4 alkyl), xe2x80x94C(xe2x95x90O)O(C1-4 alkyl),
xe2x80x94C(xe2x95x90O)( C1-4 alkyl), and xe2x80x94C(xe2x95x90O)H;
k is 1 or 2;
m is 0, 1, 2; and
n is 1 or 2.
[12] In more preferred embodiment of the present invention,
X is xe2x80x94NR10Axe2x80x94;
R1 is selected from
C2-4 alkyl substituted with Z,
C2-4 alkenyl substituted with Z,
C2-4 alkynyl substituted with Z,
C3-6 cycloalkyl substituted with Z,
aryl substituted with Z,
5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
C2-4 alkyl substituted with 0-2 R2, and
C2-4 alkenyl substituted with 0-2 R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94C(ethylenedioxy)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C( O)OR2,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
phenyl substituted with 0-5 R42;
C3-10 carbocyclic residue substituted with 0-3 R41, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
C1-4 alkoxy;
alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with xe2x80x94Oxe2x80x94xe2x80x94or xe2x80x94N(R4)xe2x80x94;
R4, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R5 is H;
R6a is selected from H, xe2x80x94OH, xe2x80x94CF3, methyl, ethyl, propyl, butyl, methoxy, and, ethoxy;
R6b is H;
R7, R8, and R9, at each occurrence, are independently selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, (C1-3 haloalkyl)oxy, and
C1-4 alkyl substituted with 0-2 R11;
R10A is selected from H, C1-6 alkyl, C1-4 alkoxy, and
C1-2 alkyl substituted with 0-1 R10B;
R10B is C3-6 cycloalkyl or
phenyl substituted with 0-3 R33;
R11is selected from
H, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94NO2,
C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and (C1-3 haloalkyl)oxy;
R33, at each occurrence, is independently selected from
H, OH, halo, CF3, and methyl;
R41, at each occurrence, is independently selected from
H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, xe2x95x90O,
C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R42, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R42, at each occurrence, is independently selected from
H, CF3, halo, OH, C2H, SO2R45, SR45, NR46R47, OR48, NO2, CN, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2,
C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
C1-4 alkyl substituted with 0-1 R43,
aryl substituted with 0-3 R44, and
5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R44;
R43 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, or pyridyl, each substituted with 0-3 R44;
R44, at each occurrence, is independently selected from H, halo, xe2x80x94OH, NR46R47, CO2H, SO2R45, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94NO2,
methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, and butoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, 1-propyl, n-butyl,
i-butyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl),
xe2x80x94SO2(methyl), xe2x80x94SO2(ethyl), xe2x80x94SO2(phenyl),
xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl),
xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
k is 1;
m is 0, 1, or 2; and
n is 1 or 2.
[13] In an even more preferred embodiment of the present invention,
X is xe2x80x94NHxe2x80x94;
R1 is selected from
ethyl substituted with Z,
propyl substituted with Z,
butyl substituted with Z,
propenyl substituted with Z,
butenyl substituted with Z,
ethyl substituted with R2,
propyl substituted with R2,
butyl substituted with R2,
propenyl substituted with R2, and
butenyl substituted with R2;
Z is selected from H,
xe2x80x94CH(OH)R2,
xe2x80x94OR2,
xe2x80x94SR2,
xe2x80x94NR2R3,
xe2x80x94C(O)R2,
xe2x80x94C(O)NR2R3,
xe2x80x94NR3C(O)R2,
xe2x80x94C(O)OR2,
xe2x80x94S(O)R2,
xe2x80x94S(O)2R2,
xe2x80x94S(O)2NR2R3, and xe2x80x94NR3S(O)2R2;
R2, at each occurrence, is independently selected from
phenyl substituted with 0-3 R42;
naphthyl substituted with 0-3 R42;
cyclopropyl substituted with 0-3 R41;
cyclobutyl substituted with 0-3 R41;
cyclopentyl substituted with 0-3 R41;
cyclohexyl substituted with 0-3 R41;
pyridyl substituted with 0-3 R41;
indolyl substituted with 0-3 R41;
indolinyl substituted with 0-3 R41;
benzimidazolyl substituted with 0-3 R41;
benzotriazolyl substituted with 0-3 R41;
benzothienyl substituted with 0-3 R41;
benzofuranyl substituted with 0-3 R41;
phthalimid-1-yl substituted with 0-3 R41;
inden-2-yl substituted with 0-3 R41;
2,3-dihydro-1H-inden-2-yl substituted with 0-3 R41;
indazolyl substituted with 0-3 R41;
tetrahydroquinolinyl substituted with 0-3 R41; and
tetrahydro-isoquinolinyl substituted with 0-3 R41;
R3, at each occurrence, is independently selected from
H, methyl, and ethyl;
R5 is H;
R6a is selected from H, xe2x80x94OH, methyl, and methoxy;
R6b is H;
R7, R8, and R9, at each occurrence, are independently selected from H, F, Cl, methyl, ethyl, methoxy, xe2x80x94CF3, and xe2x80x94OCF3;
R41, at each occurrence, is independently selected from
H, F, Cl, Br, OH, CF3, NO2, CN, xe2x95x90O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;
R42, at each occurrence, is independently selected from
H, F, Cl, Br, OH, CF3, SO2R45, SR45, NR46R47, OR48, NO2, CN, xe2x95x90O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy;
R45 is methyl, ethyl, propyl, or butyl;
R46, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl;
R47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl),
xe2x80x94SO2(methyl), xe2x80x94SO2(ethyl), xe2x80x94SO2(phenyl),
xe2x80x94C(xe2x95x90O)O(methyl),xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl),
xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
R48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, xe2x80x94C(xe2x95x90O)NH(methyl), xe2x80x94C(xe2x95x90O)NH(ethyl), xe2x80x94C(xe2x95x90O)O(methyl), xe2x80x94C(xe2x95x90O)O(ethyl), xe2x80x94C(xe2x95x90O)(methyl), xe2x80x94C(xe2x95x90O)(ethyl), and xe2x80x94C(xe2x95x90O)H;
k is 1;
m is 0, 1, or 2; and
n is 1 or 2.
[14] In another even more preferred embodiment of the present invention, the compound of Formula (I) is selected from Formula (I-a): 
wherein:
b is a single bond or a double bond;
X is xe2x80x94NR10Axe2x80x94;
R1 is selected from
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-bromo-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-(3,4-dichloro-phenyl)phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-chloro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-t-butyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3,4-difluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-methoxy-5-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-1-naphthyl),
xe2x80x94(CH2)3C(xe2x95x90O)(benzyl),
xe2x80x94(CH2)3 C(xe2x95x90O)(4-pyridyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-pyridyl),
xe2x80x94(CH2)3CH(OH)(4-fluoro-phenyl),
xe2x80x94(CH2)3CH(OH)(4-pyridyl),
xe2x80x94(CH2)3CH(OH)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3S(3-fluoro-phenyl),
xe2x80x94(CH2)3S(4-fluoro-phenyl),
xe2x80x94(CH2)3S(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3 SO2(3-fluoro-phenyl),
xe2x80x94(CH2)3 SO2(4-fluoro-phenyl),
xe2x80x94(CH2)3O(4-fluoro-phenyl),
xe2x80x94(CH2)3O(phenyl),
xe2x80x94(CH2)3O(3-pyridyl),
xe2x80x94(CH2)3O(4-pyridyl),
xe2x80x94(CH2)3O(2-NH2-phenyl),
xe2x80x94(CH2)3O(2-NH2-5-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-3-F-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-Cl-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-OH-phenyl),
xe2x80x94(CH2)3O(2-NH2-4-Br-phenyl),
xe2x80x94(CH2)3O(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3O(2-NHC(xe2x95x90O)Me-phenyl)
xe2x80x94(CH2)3NH(4-fluoro-phenyl),
xe2x80x94(CH2)3N(methyl)(4-fluoro-phenyl),
xe2x80x94(CH2)3C2(ethyl),
xe2x80x94(CH2)3C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)3C(xe2x95x90O)NH(4-fluoro-phenyl) ,
xe2x80x94(CH2)2NHC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(2-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2-fluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)3(3-indolyl),
xe2x80x94(CH2)3(1-methyl-3-indolyl),
xe2x80x94(CH2)3(1-indolyl),
xe2x80x94(CH2)3(1-indolinyl)
xe2x80x94(CH2)3(1-benzimidazolyl)
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-1-yl),
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)2(1H-1,2,3-benzotriazol-1-yl),
xe2x80x94(CH2)2(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)3(3,4 dihydro-1(2H)-quinolinyl),
xe2x80x94(CH2)2C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2C(xe2x95x90O)NH(4-fluoro-phenyl),
xe2x80x94CH2CH2(3-indolyl),
xe2x80x94CH2CH2(1-phthalimidyl),
xe2x80x94(CH2)4C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)4CO2(ethyl),
xe2x80x94(CH2)4C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)4(cyclohexyl),
xe2x80x94(CH2)3CH(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90C(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90CMe(4-F-phenyl),
xe2x80x94CH2)3CH (4-fluoro-phenyl)2,
xe2x80x94(CH2CH2CHxe2x95x90C(4-fluoro-phenyl)2,
xe2x80x94(CH2)2 (2,3-dihydro-1H-inden-2-yl) ,
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-5-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-3-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Cl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-OH-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Br-phenyl),
xe2x80x94(CH2)3(1H-indazol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(7-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(6-Cl-1H-indazol-3-yl),
xe2x80x94(CH2)3(6-Br-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHMe-phenyl),
xe2x80x94(CH2)3(1-benzothien-3-yl),
xe2x80x94(CH2)3(6-F-1H-indol-1-yl)
xe2x80x94(CH2)3(5-F-1H-indol-1-yl),
xe2x80x94(CH2)3(6-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(5-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(6-F-1H-indol-3-yl),
xe2x80x94(CH2)3 (5-F-1H-indol-3-yl),
xe2x80x94(CH2 )3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3 (9H-purin-9-yl),
xe2x80x94(CH2)3(7H-purin-7-yl),
xe2x80x94(CH2)3(6-F-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCO2Et-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)NHEt-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCHO-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-OH-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-MeS-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)CO2Me,
xe2x80x94(CH2)2C(Me)CH(OH)(4-F-phenyl)2,
xe2x80x94(CH2)2C(Me)CH(OH)(4-Cl-phenyl)2,
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-MeO-4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(3-Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-Me-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)phenyl, 
R7, R8, and R9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenyl, benzyl,
HC(xe2x95x90O)xe2x80x94, methylC(xe2x95x90O)xe2x80x94, ethylC(xe2x95x90O)xe2x80x94, propylC(xe2x95x90O)xe2x80x94,
isopropylC(xe2x95x90O)xe2x80x94, n-butylC(xe2x95x90O)xe2x80x94, isobutylC(xe2x95x90O)xe2x80x94,
secbutylC(xe2x95x90O)xe2x80x94, tertbutylC(xe2x95x90O)xe2x80x94, phenylC(xe2x95x90O)xe2x80x94,
methylC(xe2x95x90O)NHxe2x80x94, ethylC(xe2x95x90O)NH xe2x80x94, propylC(xe2x95x90O)NHxe2x80x94,
isopropylC(xe2x95x90O)NHxe2x80x94, n-butylC(xe2x95x90O)NHxe2x80x94, isobutylC(xe2x95x90O)NHxe2x80x94,
secbutylC(xe2x95x90O)NHxe2x80x94, tertbutylC(xe2x95x90O)NHxe2x80x94, phenylC(xe2x95x90O)NHxe2x80x94,
methylamino-, ethylamino-, propylamino-, isopropylamino-,
n-butylamnino-, isobutylamino-, secbutylamino-,
tertbutylamino-, phenylamino-,
provided that two of substituents R7, R8 and R9, are independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy;
R10A is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl, 2-methylbenzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl, 2-trifluoromethoxybenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl, 3-methylbenzyl, 3-trifluoromethylbenzyl, 3-methoxybenzyl, 3-trifluoromethoxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, and 4-trifluoromethoxybenzyl;
k is 1 or 2;
m is 1 or 2; and
n is 1 or 2.
[15] In another even more preferred embodiment of the present invention, the compound of Formula (I) is selected from Formula (IV-a): 
wherein:
b is a single bond, wherein the bridge hydrogens are in a cis position;
R1 is selected from
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-bromo-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-methoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-(3,4-dichloro-phenyl)phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-4-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-chloro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-methyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-t-butyl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3,4-difluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-methoxy-5-fluoro-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-fluoro-1-naphthyl),
xe2x80x94(CH2)3C(xe2x95x90O)(benzyl),
xe2x80x94(CH2)3C(xe2x95x90O)(4-pyridyl),
xe2x80x94(CH2)3C(xe2x95x90O)(3-pyridyl),
xe2x80x94(CH2)3CH(OH)(4-fluoro-phenyl),
xe2x80x94(CH2)3CH(OH)(4-pyridyl),
xe2x80x94(CH2)3CH(OH)(2,3-dimethoxy-phenyl),
xe2x80x94(CH2)3S(3-fluoro-phenyl),
xe2x80x94(CH2)3S(4-fluoro-phenyl),
xe2x80x94(CH2)3S(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)3SO2(3-fluoro-phenyl),
xe2x80x94(CH2)3SO2(4-fluoro-phenyl),
xe2x80x94(CH2)3O(4-fluoro-phenyl),
xe2x80x94(CH2)3O(phenyl)
xe2x80x94(CH2)3NH(4-fluoro-phenyl),
xe2x80x94(CH2)3N(methyl)(4-fluoro-phenyl),
xe2x80x94(CH2)3CO2(ethyl),
xe2x80x94(CH2)3C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)3C(xe2x95x90O)NH(4-fluoro-phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(phenyl),
xe2x80x94(CH2)2NHC(xe2x95x90O)(2-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2-fluoro-phenyl) ,
xe2x80x94(CH2)2NHC(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(4-fluoro-phenyl)
xe2x80x94(CH2)2NHC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)2NMeC(xe2x95x90O)(2,4-difluoro-phenyl),
xe2x80x94(CH2)3(3-indolyl),
xe2x80x94(CH2)3(1-methyl-3-indolyl)
xe2x80x94(CH2)3(1-indolyl),
xe2x80x94(CH2)3(1-indolinyl),
xe2x80x94(CH2)3(1-benzimidazolyl),
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-1-yl),
xe2x80x94(CH2)3(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)2(1H-1,2,3-benzotriazol-1-yl)
xe2x80x94(CH2)2(1H-1,2,3-benzotriazol-2-yl),
xe2x80x94(CH2)3(3,4 dihydro-1(2H)-quinolinyl),
xe2x80x94(CH2)2C(xe2x95x90O)(4-fluoro-phenyl),
xe2x80x94(CH2)2C(xe2x95x90O)NH(4-fluoro-phenyl)
xe2x80x94CH2CH2(3-indolyl),
xe2x80x94CH2CH2(1-phthalimidyl) ,
xe2x80x94(CH2)4C(xe2x95x90O)N(methyl)(methoxy),
xe2x80x94(CH2)4C2(ethyl),
xe2x80x94(CH2)4C(xe2x95x90O)(phenyl),
xe2x80x94(CH2)4(cyclohexyl),
xe2x80x94(CH2)3CH(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90C(phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90CMe(4-F-phenyl),
xe2x80x94(CH2)3CH(4-fuoro-phenyl)2,
xe2x80x94CH2CH2CHxe2x95x90C(4-fluoro-phenyl)2,
xe2x80x94(CH2)2(2,3-dihydro-1H-inden-2-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-5-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-3-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Cl-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-OH-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NH2-4-Br-phenyl),
xe2x80x94(CH2)3(1H-indazol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(7-F-1H-indazol-3-yl),
xe2x80x94(CH2)3(6-Cl-1H-indazol-3-yl) ,
xe2x80x94(CH2)3(6-Br-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHMe-phenyl),
xe2x80x94(CH2)3(1-benzothien-3-yl),
xe2x80x94(CH2)3(6-F-1H-indol-1-yl),
xe2x80x94(CH2)3(5-F-1H-indol-1-yl) ,
xe2x80x94(CH2)3(6-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(5-F-2,3-dihydro-1H-indol-1-yl),
xe2x80x94(CH2)3(6-F-1H-indol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3(5-F-1H-indol-3-yl),
xe2x80x94(CH2)3(9H-purin-9-yl),
xe2x80x94(CH2)3(7H-purin-7-yl),
xe2x80x94(CH2)3(6-F-1H-indazol-3-yl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)Me-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCO2Et-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHC(xe2x95x90O)NHEt-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHCHO-4-F-phenyl),
xe2x80x94(CH2)3(xe2x95x90O)(2-OH-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-MeS-4-F-phenyl),
xe2x80x94(CH2)3C(xe2x95x90O)(2-NHSO2Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)CO2Me,
xe2x80x94(H2)2C(Me)CH(OH)(4-F-phenyl)2,
xe2x80x94(CH2)2C(Me)CH(OH)(4-Cl-phenyl)2,
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(4-F-phenyl)2,
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-MeO-4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(3-Me-4-F-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)(2-Me-phenyl),
xe2x80x94(CH2)2C(Me)C(xe2x95x90O)phenyl, 
R7, R8, and R9, at each occurrence, are independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylC(xe2x95x90O)xe2x80x94, ethylC(xe2x95x90O)xe2x80x94, propylC(xe2x95x90O)xe2x80x94, isopropylC(xe2x95x90O)xe2x80x94, methylC(xe2x95x90O)NHxe2x80x94, ethylC(xe2x95x90O)NHxe2x80x94, propylC(xe2x95x90O)NHxe2x80x94, isopropylC(xe2x95x90O)NH, methylamino-, ethylamino-, propylamino-, and isopropylamino-,
provided that two of substituents R7, R8, and R9, are independently selected from hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;
R10A is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 2-bromobenzyl, 2-methylbenzyl, 2-trifluoromethylbenzyl, 2-methoxybenzyl, 2-trifluoromethoxybenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-bromobenzyl, 3-methylbenzyl, 3-trifluoromethylbenzyl, 3-methoxybenzyl, 3-trifluoromethoxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, and 4-trifluoromethoxybenzyl;
m is 1 or 2; and
n is 1 or 2.
In an even further more preferred embodiment of the present invention, are compounds of Formula (I) selected from Table 1.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment a central nervous system disorder comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is a 5HT2a antagonist or a 5HT2c agonist.
In a preferred embodiment the compound is a 5HT2a antagonist.
In another preferred embodiment the compound is a 5HT2c agonist.
In a more preferred embodiment the present invention provides a method for the treatment central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In a further preferred embodiment the central nervous system disorder comprises obesity.
In another further preferred embodiment the central nervous system disorder comprises schizophrenia.
In another further preferred embodiment the central nervous system disorder comprises depression.
In another further preferred embodiment the central nervous system disorder comprises anxiety.
In a fourth embodiment the present invention provides novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for use in therapy.
In a fifth embodiment the present invention provides the use of novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for the manufacture of a medicament for the treatment of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, and gastrointestinal disorders.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The numbering of the tetracyclic ring-system present in the compounds of Formula (I), as defined by nomenclature known to one skilled in the art, is shown for two examples in Formula (Ixe2x80x2), when k is 1, m is 1, and n is 1; and in Formula (Ixe2x80x3), when k is 1, m is 1, and n is 2:
The tetracyclic ring-system present in compounds of Formula (I) occur as xe2x80x9ccisxe2x80x9d or xe2x80x9ctransxe2x80x9d isomers when the carbon-carbon bond b in Formula (I) is a single bond. As such, the terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d, in conjunction with the tetracyclic ring structure, refer to the configuration of hydrogen atoms on carbon atoms 7a and 11a in Formula (Ixe2x80x2) or, for example, on carbon atoms 8a and 12a in Formula (Ixe2x80x3), above. When both hydrogens are on the same side of the mean plane determined by the octahydro tetracyclic moiety then the configuration is designated xe2x80x9ccisxe2x80x9d, if not, the configuration is designated xe2x80x9ctransxe2x80x9d. It is understood that the above example is for demonstrative puproses only and not intended to limit the scope of the tetracyclic ring-system present in compounds of Formula (I). As such, it is understood that one skilled in the art of organic chemistry can apply the above numbering system to other values of k, m, and n in the scope of compounds of Formula (I) to deterine the appropriate numbering. Additional Examples of the numbering of the tetracyclic ring-system are further provided below in the synthetic Examples. Lastly, it is understood that the use of xe2x80x9ccisxe2x80x9d or xe2x80x9ctransxe2x80x9d in the identification of the tetracyclic ring-system is not meant to construe the configuration of any other cis or trans geometric isomer in the molecule, for example, cis or trans butene.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R2) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R2, then said group may optionally be substituted with up to two R2 groups and R2 at each occurrence is selected independently from the definition of R2. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, xe2x80x9calkylthioxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulpher bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9cbicyclic heterocyclic ring systemxe2x80x9d is intended to mean a stable 9- to 10-membered bicyclic heterocyclic ring formed from the substituent R12R13, which is partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms, a nitrogen atom, and 1 or 2 additional heteroatoms independently selected from the group consisting of N, O and S. The additional nitrogen or sulfur heteroatoms may optionally be oxidized. The heterocyclic ring is attached to its pendant group by the nitrogen atom of the group NR12R13 and for which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. The term xe2x80x9cbicyclic heterocyclic ring systemxe2x80x9d is intended to be a subset of the term xe2x80x9cheterocyclic ring systemxe2x80x9d. Preferred examples of a 9- to 10- membered bicyclic heterocyclic ring system are benzimidazolyl, benzimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl, dihydrodioxobenzthiazolyl, benzisoxazolinyl, 1H-indazolyl, indolyl, indolinyl, isoindolinyl, tetrahydro-isoquinolinyl, tetrahydro-quinolinyl, and benzotriazolyl.
Additionally, a subclass of preferred heterocycles are heterocycles which function as an isostere of a cyclic but non-heterocyclic substitutent such as xe2x80x94CH2xe2x80x94C(xe2x95x90O)-phenyl. Preferred examples of such heterocycles include, but are not limited to, benzimidazolyl, benzofuranyl, 30 benzothiophenyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, furanyl, imidazolinyl, 1H-indazolyl, indolinyl, isoindolinyl, isoquinolinyl, oxazolyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, thiophenyl, and 1,2,3-triazolyl.
As used herein, the term xe2x80x9carylxe2x80x9d, or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl, pyridinyl and naphthyl.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Throughout the details of the invention, the following abbreviations are used with the following meanings:
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
The preparation of compounds of Formula (I) of the present invention may be carried out in a convergent or sequential synthetic manner. Detailed synthetic preparations of the compounds of Formula (I) are shown in the following reaction schemes. The skills required in preparation and purification of the compounds of Formula (I) and the intermediates leading to these compounds are known to those in the art. Purification procedures include, but are not limited to, normal or reverse phase chromatography, crystallization, and distillation.
Several methods for the preparation of the compounds of the present invention are illustrated in the schemes and examples shown below. The substitutions are as described and defined above.
Compounds of Formula (I) of this invention may be prepared as shown in Scheme 1. Thus, preparation of an aryl hydrazine (III) is accomplished, for example, by treatment of a corresponding substituted aniline (II) with NaNO2 followed by reduction of the N-nitroso intermediate with a reducing agent such as LAH or zinc and an organic acid, such as acetic acid or trifluoroacetic acid at low temperature. Assembly of the core tetracyclic intermediate indole (V) is accomplished by Fischer indole cyclization of the aryl hydrazine and a suitably substituted ketone (i.e. (IV)) by methods described by, but not limited to, R. J. Sundberg, xe2x80x9cIndoles, Best Synthetic Methodsxe2x80x9d 1996, Academic Press, San Diego, Calif. For example, treatment of the aryl hydrazine (III) as the free base or the corresponding mineral acid salt with the ketone (IV) (R1xe2x95x90H, Bn, CBZ, CO2Et, etc) in an alcoholic solvent in the presence of mineral acid affords the indoles (V) as the free bases (after treatment with aq. NaOH). Reduction of the indoles 0to the corresponding cis or trans substituted dihydroindoles is accomplished by, for example, treatment with hydrogen in the presence of a catalyst such as platinum oxide or palladium on carbon, or with a metal such as zinc and a mineral acid such as hydrochloric acid, or with sodium and liquid ammonia, or with borane-amine complex such as borane-triethylamine in tetrahydofuran, or preferably by treatment with NaCNBH3 in an acid such as acetic or trifluoroacetic acid.
The corresponding enantiomers can be isolated by separation of the racemic mixture of (I) on a chiral stationary phase column utilizing normal or reverse phase HPLC techniques, the details of which are described in the examples. Alternatively, a diastereomeric mixture of (I) can be prepared by treatment of (I, R1xe2x95x90H) with an appropriate chiral acid (or suitably activated derivative), for example dibenzoyl tartrate or the like (see, for example, Kinbara, K., et. al., J. Chem . Soc., Perkin Trans. 2, 1996, 2615; and Tomori, H., et. al., Bull. Chem. Soc. Jpn., 1996, 3581). The diastereomers would then be separated by traditional techniques (i.e. silica chromatography, crystallization, HPLC, etc) followed by removal of the chiral auxiliary to afford enantiomerically pure (I).
In the cases where the carboline nitrogen has been protected (VI) (i.e. R1=Boc, Bn, CBZ, CO2R), it may be removed under a variety of conditions as described in Greene, T. W., Wuts, P. G. W., xe2x80x9cProtective Groups in Organic Synthesis, 2nd Editionxe2x80x9d, John Wiley and Sons, Inc., New York, pages 309-405, 1991. The free secondary amine could then be alkylated, for example, by treatment with a suitably substituted alkyl halide (R1Cl, or R1I) and a base to afford additional compounds of type (I), as described, for example, by Glennon, R. A., et. al., Med. Chem. Res., 1996, 197.
Alternatively, compounds of Formula (I) can be prepared as described in Scheme 2. Treatment of an ortho halonitrobenzene compound (VII) with a nucleophilic alkyl halide (Xxe2x95x90OH, SH, NHR, (VIII)) (as described by Kharasch, N., Langford, R. B., J. Org. Chem., 1963, 1903) and a suitable base followed by subsequent reduction of the corresponding nitroaryl derivative to the aniline (IX). The reduction may be accomplished with a variety of reducing agents, for example, LAH, SnCl2, NaBH4, N2H4, etc. or with hydrogen in the presence of a suitable catalyst, such as palladium on carbon, or platinum oxide, etc., (see Hudlicky, M., xe2x80x9cReductions in Organic Chemistryxe2x80x9d, Ellis Horwood, Ltd., Chichester, UK, 1984). Formation of the aryl hydrazine (X) may be accomplished as described previously in Scheme 1 or more directly by treatment of the aniline (IX) with aq. hydrochloric acid, stannous chloride and NaNO2 at room temperature (see, Buck, J. S., Ide, W. S., Org. Syn., Coll. Vol., 2, 1943, 130). This primary aryl hydrazine (X) can then be cyclized under Fischer indole cyclization conditions as detailed above for compound (V), to afford the indole (XI) as the corresponding salt. Upon treatment of the indole (XI) with a base such potassium hydroxide or potassium t-butoxide in a solvent such as DME or THF affords the tetracyclic indole intermediates (V). These indoles can also be reduced to the corresponding cis or trans indolines (I) as described previously in Scheme 1.
Still another related route to compounds of Formula (I) is shown in Scheme 3. Initiating the synthesis with a nitrobenzene derivative such as (XII), this approach allows for a variety of derivatization. More highly substituted nitrobenzenes can be obtained by traditional synthetic manipulation (i.e. aromatic substitution) and are known by those in the art (see Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, New York, 1989): Treatment of nitrobenzene derivative with a reducing agent such as LAH, etc., as described previously (see Hudlicky, et. al.), affords the corresponding aniline intermediate. Subsequent formation of the hydrazine followed by Fischer indole cyclization with a suitably functionalized ketone as described above (i.e. Scheme 1, (III) to (V)) affords the g-carboline indole (XIII). At this point the fused ring may be appended by condensation of a haloalkyl carboxylic acid or a related activated carboxylic acid (i.e. acid chloride, mixed anhydride, etc.) such as (XIV). Reduction of the resultant heterocyclic carbonyl may be effected with various reducing agents, for example, sodium borohydride, diisobutyl aluminum hydride and the like (see Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, New York, 1989 and/or Hudlicky, M., xe2x80x9cReductions in Organic Chemistryxe2x80x9d, Ellis Horwood, Ltd., Chichester, UK, 1984) to afford the tetracyclic indoles (V). Further reduction of the indole (V) to the indolines (I) is as described previously in Scheme 1.
Preparation of the aniline precursors (II) to the Fischer indole cyclizations is shown in Scheme 4. Treatment of a suitably ortho-functionalized aniline (XVI) with a chloroalkyl carboxylic acid or ester (or equivalent substrate, i.e. acrylic acid, acryloyl chloride, etc.) and concomitant condensation, followed by reduction of the resultant heterocyclic carbonyl with a reducing agent such as LAH, DIBAL, or Red-Al affords the fused heterocyclic benzene derivatives (II). More diverse intermediates of (II) may be obtained by formation of the ortho substitiuted aniline from the corresponding ortho substituted nitobenzenes and concomitant reduction of the nitro moiety as described above. Furthermore, aromatic substitution of the fluoro (or other halo derived nitrobenzene) functionality of (XV) for an oxygen, or sulphur moiety is accomplished, for example, by treatment of (XV) with a nucleophile, such as sodium sulfide or an alcohol, followed by formation of the requisite thiophenol or phenol, respectively, using standard techniques known by those in the art (see Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, New York, 1989, page 481). Reduction of the nitro as before affords the substituted anilines (XVI). 
An alternate approach to the substituted fused anilines (II) is shown in Scheme 5. Treatment of the phenol (Xxe2x95x90OH), thiophenol (Xxe2x95x90SH), or other nucleophilically aromatic substituted derivative (XVII) with, for example, a haloalkyl carboxylic acid (or equivalent activated haloalkylcarboxylic acid, (i.e. acid halide, mixed anhydride, acrylic acid, acryloyl chloride, etc.), affords the derivative (XVIII) which when treated under Friedel-Crafts acylation conditions (see Ed. G. A. Olah, xe2x80x9cFriedel-Crafts and Related Reactionsxe2x80x9d, J. Wiley and Sons, New York, 1964, Vol 3, Pts 1 and 2 or Chem. Rev., 1955, 229, or Olah, G. A., xe2x80x9cFriedel-Crafts Chemistryxe2x80x9d, Wiley Interscience, New York, 1973, for varying conditions and protocols), i.e. strong Lewis acids (AlCl3, FeCl3, etc.), affords the cyclic alkylphenones (XIX). Incorporation of the nitrogen functionality can be accomplished in several ways. For example, Schmidt rearrangement (as described by Smith, P. A. S., J. Am. Chem. Soc., 1948, 320) is effected by treatment of the carbonyl derivative (XIX) with NaN3 and methanesulfonic acid to afford the bicyclic lactam (XX). Alternatively, this transformation may be carried out under Hoffmann rearrangement protocol (see, for example, Dike, S. Y., et. al., Bioorg. Med. Chem. Lett., 1991, 383), by initial formation of the oxime derivative of (XXI) by treatment with hydroxylamine hydrochloride. Subsequent rearrangement to the lactam is efficiently accomplished by heating in polyphosphoric acid to afford the lactam (XX). Reduction of the lactam (XX) can be accomplished with a variety of reducing agents, for example, DIBAL, Red-Al and the like to afford the aniline (II). 
The preparation of compounds of Formula (I) with additional diversity of functionalization of the aromatic A ring of the tetracycle is shown in Scheme 6 and Scheme 7 and described here. Due to the nature of the synthetic route of Scheme 1 to derivatives of Formula (I), compounds with halogen substituents on the A-ring are difficult to prepare. However, bromination of the indolines (I, R8xe2x95x90H) when the amine is protected, for example, with the Boc or CBZ protecting groups, with, for example, NBS in DMF affords the R8 brominated derivatives (XXII). These activated aryl derivatives (XXII) act as excellent counterparts for a number of important synthetic transformations.
For example, biaryl coupling is accomplished under Suzuki coupling protocol. For a review and leading references of palladium catalyzed cross coupling reactions, see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457. One such procedure entails treatment of the aryl bromide (XXII) with a functionalized aryl boronic acid (XXIII) in the presence of a catalytic Pd(0) species, such as Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2, Pd2(dba)3 and a suitable ligand such as PPh3, AsPh3, etc., or other such Pd(0) catalyst, and a base such as Na2CO3 or Et3N in a suitable solvent such as DMF, toluene, THF, DME or the like, to afford the indolines (XXIV). Alternatively formation of the indole boronic acid from the bromine derivative (XXII) (i.e. (I, R8xe2x95x90B(OH)2)) would allow for greater diversity in the subsequent coupling of this indole boronic acid with commercially available haloaromatic derivatives in a similar Suzuki coupling strategy as-described above to afford the indolines (XXIV). 
Similarly biaryl coupling of the bromine derivatives (XXV), readily obtained by the synthetic sequence exemplified in Scheme 2, (starting with the suitably functionalized bromo nitrobenzenes (II)), is shown in Scheme 7. This approach allows for the preparation of biaryl indoles as well as the corresponding indoline derivatives. Protection of the amine functionality must be carried out if R1xe2x95x90H (see Greene et.al for protections of amines). This is readily accomplished, for example, by treatment of bromo derivatives (XXV) with (Boc)2O in aqueous sodium hydroxide and dioxane. Subsequent Suzuki coupling with a variety of aryl boronic acids is carried out as described above in Scheme 6, to afford the biaryl adducts (XXVI). This protocol is amenable to R7, R8, and R9 bromide, iodide, triflates, and/or diazo derivatives (see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457, for a review of aryl couplings). 
Furthermore and as an extension of this approach to a rapid preparation of a large array of biaryl indole and indoline derivatives, these bromide derivatives (XXV) can be bound to a solid support and the Suzuki couplings can be carried out on solid support (see XXVIII) as illustrated in Scheme 8. Towards that end treatment of indoline (XXV) with TFA in CH2Cl2, to remove the Boc protecting group, followed extraction from aqueous base provides the free amine (XXXVII). The free amine can be loaded onto a suitable solid support such as (XXVIII) using conditions well known to those skilled in the art. Thus, p-nitrophenylchloroformate Wang resin (XXVIII) which can be obtained commercially from sources such as Novabiochem, Inc. is swollen in a suitable solvent such as N-methyl pyrrolidinone and treated with 1.5 equiv. of amine to afford the functionalized resin (XXIX). Suzuki couplings are then carried out in array format by treatment of resins (XXIX) with a suitable palladium source such as Pd(PPh3)4 or Pd(dppf)C12 and a suitable base such as 2M aqueous K2CO3 or Na2CO3or triethylamine with an excess (typically 5 equivalents) of an aryl boronic acid (procedures for solid-phase Suzuki and other palladium couplings are well-known by those in the art, see for instance L. A. Thompson and J. A. .Ellman, Chem. Rev. 1996, 96, (1), 555-600). The coupling may be repeated to ensure complete conversion to the desired coupled product. Cleavage from the solid support by treatment with TFA affords the corresponding indoles and indolines (XXX) as their TFA salts. 
In addition, there exists a wide range of procedures and protocols for functionalizing haloaromatics, aryldiazonium and aryltriflate compounds. These procedures are well known by those in the art and described, for example, by Stanforth, S. P., Tetrahedron, 1998, 263; Buchwald, S. L., et. al., J. Am. Chem. Soc., 1998, 9722; Stille, J. K., et. al., J. Am. Chem. Soc., 1984, 7500. Among these procedures are biaryl couplings, alkylations, acylations, aminations, and amidations. The power of palladium catalyzed functionalization of aromatic cores has been explored in depth in the last decade. An excellent review of this field can be found in J. Tsuji, xe2x80x9cPalladium Reagents and Catalysts, Innovations in Organic Synthesisxe2x80x9d, J. Wiley and Sons, New York, 1995.
One such method to prepare compounds of Formula (I) with substituted R1 sidechains in a more direct manner is shown in Scheme 9. Alkylation of the indole or indoline derivatives (I, R1xe2x95x90H) with a haloalkyl ester, such as ClCH2(CH2)pCO2Me, in the presence of NaI or KI and a base such as K2CO3, Na2CO3 or the like, in dioxane or THF or other such solvent while heating (see Glennon, R. A., et. al., Med. Chem. Res., 1996, 197) affords the R1 alkylated esters. Subsequent formation of the activated amides (XXXI) is accomplished by treatment of the ester with N,O-dimethylhydroxylamine hydrochloride and a Lewis acid such as trimethylaluminum or triethylaluminum in toluene (see, for example, Golec, J. M. C., et. al., Tetrahedron, 1994, 809) at 0xc2x0 C. Treatment of the amide (XXXI) with a variety of organometallic agents, such as Grignard reagents R1aMgBr, alkyl and aryl lithium reagents etc. (see Sibi, M. P., et. al., Tetrahedron Lett., 1992, 1941; and more generally House, H. O., Modern Synthetic Reactions, W. A. Benjamin, Inc., Menlo Park, Calif., 1972), in a suitable solvent such as THF, ether, etc. at low temperatures affords the substituted ketones (XXXII). 
Preparation of compounds of Formula (I) where m=0, k=1 is outlined in Scheme 10 and described here. Fischer indole cyclization of the previously described hydrazine (III) with a known protected 2,3-dioxopyrolidine (Carlson, E. H., et. al., J. Org. Chem., 1956, 1087) under a variety of typical cyclization conditions affords the tetracyclic indole (XXXIII). The reduction may be accomplished with a variety of reducing agents, for example, LAH, DIBAL, etc., to yield the pyrole fused indole (XXXIV). This derivative can then be deprotected and subsequently alkylated as described previously (see Greene, T. W., Wuts, P. G. W., xe2x80x9cProtective Groups in Organic Synthesis, 2nd Editionxe2x80x9d, John Wiley and Sons, Inc., New York, 1991, and Scheme 1), to give the R1 alkylated indole analogs (XXXV). Alternatively, reduction of the indole to the indoline, as described previously (see Scheme 1), followed by deprotection of the benzyl group to give (XXXVI) and alkylation gives access to the corresponding R1 alkylated indoline derivatives (XXXVII). All the previously described methods to functionalize the aromatic ring, and to afford derivatives of varying R1 sidecahins are applicable to these cores. 